Process for preparing biodegradable polymers of high molecular weight

Abstract

A novel method for the preparation of biodegradable polymers is disclosed. The method produces polymers of high molecular weight and particularly allows for stirring throughout the polymerization reaction.

Claims

1. A method of polymerization of lactide and glycolide, comprising the step of performing polymerization under stirring, in the presence of an organic solvent, a metal catalyst and optionally a co-initiator, wherein the polymerization is performed in a closed sealed reactor system, which does not allow air or other gas exchange between an inner and an outer part of it once it is sealed.

2. A method according to claim 1, wherein the metal catalyst is selected from tin, zinc, aluminum catalysts.

3. A method according to claim 2, wherein the metal catalyst is selected from halides, alkoxides and carboxylic acid salts of tin, zinc and aluminum.

4. A method according to claim 3, wherein the metal catalyst is selected from tin and aluminum alkoxides and carboxylic acid salts.

5. A method according to claim 4, wherein the metal catalyst is selected from tin alkoxides and carboxylic acid salts.

6. A method according to claim 1, wherein the solvent is selected from aliphatic and aromatic hydrocarbons, halogenated aliphatic and aromatic hydrocarbons and aliphatic and aromatic ethers.

7. A method according to claim 1, wherein the ratio of he solvent with respect to the combined mass of the monomers is at least 1 ml per gram.

8. A method according to claim 1, wherein the Mw of the resulting polymer is at least 5×10 Da, as measured by GPC method.

9. A method according to claim 1, wherein the co-initiator is a mono- , di- or polyalcohol with 1-20 carbon atoms.

10. A method according to claim 1, wherein the polymer produced is linear.

11. A method according to claim 1, wherein the polymer produced is branched.

12. A method for producing a drug delivery system comprising an active pharmaceutical ingredient, said method comprising the step of producing a polymer with a method as defined in claim 1.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) It has surprisingly been found that the polymerization of mixtures of lactide and glycolide can be performed in the presence of a solvent, whereby stiffing is conveniently applied, the reaction time is limited to a few hours and the polymer product exhibits a high molecular weight, suitable for biomedical applications.

(2) According to an embodiment of the invention, there is provided a method of polymerization of mixtures of lactide and glycolide, comprising the step of performing polymerization under stirring in the presence of an organic solvent, a metal catalyst (initiator) and optionally a co-initiator, wherein the polymerization is performed in a closed system.

(3) Lactide, as lactic acid, exists in the form of diastereomers. Lactic acid can be L-lactic acid, D-lactic acid or D, L-lactic acid (racemate). Likewise, the lactide can be L-lactide, D-lactide, D, L-lactide (racemate) or meso-lactide.

(4) The polymers produced according to the method of the present invention are copolymers. The skilled person understands that the method disclosed herein is not limited to a specific type of copolymer and the type which is produced may vary, depending on the conditions employed. Non-limiting examples of copolymer types are random copolymers, alternating copolymers, gradient copolymer, tapered copolymer, block copolymers.

(5) Aprotic solvents are preferable. More preferable are aliphatic and aromatic hydrocarbons, halogenated aliphatic and aromatic hydrocarbons and aliphatic and aromatic ethers. Even more preferable are aromatic hydrocarbons and halogenated aliphatic hydrocarbons. Still more preferable is toluene and chloroform.

(6) The presence of a solvent allows the polymerization to proceed under stirring conditions, as a consequence of the lower viscosity of the mass. Additionally, the monomers' solubility increases as the temperature rises and this dissolution phenomenon is in favor of the polymerization reaction. The presence of the solvent provides for better heat transfer and thermal control, better mixing and increased homogeneity of the polymerization mass. It also helps avoid creation of hot spots, which are responsible for heat dissipation problems and discoloration of the polymer. A further advantage is the easier manipulation of the polymerization conditions. Additives can easily be used and there is a broad range of design possibilities. Thus, various properties can be achieved and it is easier to modify the process (e.g. addition of nano-particles).

(7) The amount of the solvent used may be tuned according to the other reaction parameters and the desired properties of the produced polymers. In a preferred embodiment, the ratio of the solvent with respect to the combined mass of the monomers is at least 1 ml per gram. More preferable are at least 2 ml per gram. Still more preferable are at least 4 ml per gram. Even more preferable are at least 8 ml per gram.

(8) The apparatus which is used for the polymerization reaction operates as a closed system. Such an apparatus does not allow air (or other gas) exchange between the inner and the outer part of it once it is sealed. Reactors with this feature are very common in the industry as well as in most laboratories. A common type of such apparatuses are autoclaves. All these apparatuses tolerate a certain degree of internal pressure, depending on their characteristics. Accordingly, a reaction performed in such apparatuses or equipment may be performed beyond the boiling point of the solvent, as the increase of the pressure allows the solvent (or at least its major part) to remain in the liquid phase.

(9) The temperature at which the polymerization reaction is performed depends on the desired polymerization rate and subsequently on the target molecular weight of the resulting polymer. Notably, stiffing allows a more flexible choice of temperature with respect to bulk polymerization, because the solvent dissolves, at least partially, the monomers and their melting is not a prerequisite. This is important for industrial purposes, as the higher the temperature to be reached, the more demanding and energy consuming the process is.

(10) Surprisingly, the reaction time is considerably shorter and provides polymers of higher molecular weight compared to prior art processes which employ organic solvents.

(11) The polymerization reaction occurs in the presence of a metal catalyst. Several catalysts and initiators have been tested in glycolide/lactide copolymerization. Early studies include the testing of commercially available chlorides, alkoxides, oxides or sulfides of main groups and transition metals (Sn, Al, Zr, Ti, Pd, Cd, and Zn).

(12) Preferable metal catalysts are tin, zinc, aluminum. More preferable are halides, alkoxides and carboxylic acid salts of tin, zinc and aluminum. Even more preferable are tin and aluminum alkoxides and carboxylic acid salts. Even more preferable are tin alkoxides and carboxylic acid salts. Still more preferable is tin (II) 2-ethylhexanoate [Sn(Oct).sub.2].

(13) Co-initiators suitable for the present invention are aliphatic mono-, di- or polyalcohols. Alternatively, the present method may be performed without a co-initiator, whereby any moisture may initiate the polymerization reaction. Therefore, the presence of a co-initiator is optional and depends on the sought properties of the end polymer. The skilled person understands that the type of the co-initiator has an effect to the chain length of the polymer as well as to the type of the polymer. Such types are, for example linear, branched and cross-linked polymers. Branched polymers include more specific types such as star polymers, graft polymer, dendrimers and hyperbranched polymers.

(14) The scope of the present invention is therefore not limited to a specific type of polymer. According to the present invention, linear, branched or cross-linked polymers may be prepared, depending on the conditions employed by the skilled person.

(15) Preferable co-initiators are mono-, di- or polyalcohols with 1-20 carbon atoms. More preferable are methanol, butanol, 1,4-butanediol, 1-dodecanol, glucose, di(trimethylopropane), pentaerythritol, glycerol. Alcohols with a single —OH group or two —OH groups are normally used for linear polymers whereas polyalcohols are used for branched-type polymers.

(16) The feed ratio of the monomers depends on the type of the polymer that is sought to be produced and its applications and it is adjusted accordingly. The scope of the present invention, therefore embraces polymers of various composition, resulting from different ratios of the two monomers, i.e. glycolide and lactide.

(17) The composition of PLGA is one key property which needs to be adequately controlled by the method of polymerization. It can be determined by controlling the feed ratio of the monomers. However, control of the molecular weight of PLGA, another key feature of the polymer requires extra effort. Monomer purity, catalyst concentration, polymerization temperature, polymerization time, catalyst concentration, degree of vacuum, and the amount of molecular weight controller (hydroxyl containing compound or co-initiator) added, all affect the molecular weight of the resulting polymer.

(18) Advantageously, the method disclosed herein allows access to polymers of high molecular weight, i.e. tens or hundreds of thousands Da. This is desirable for the production of materials for a wide range of biomedical applications including drug release systems, sutures, orthopedic applications, tissue engineering, implants.

(19) However, depending on the various factors of the reaction, the molecular weight of the resulting polymer can be adjusted as desired. The scope of the present invention, therefore embraces polymers of various molecular weights.

(20) The molecular weight (MW) of the polymers may be measured by a variety of methods. Gel Permeation Chromatography (GPC) is employed for the determination of the molecular weight distribution of the polymers. A universal calibration curve, constructed with polystyrene standards (PolymerLabs) of known molecular weights, was employed for the determination of the MWD (Molecular Weight Distribution) of the unknown PLGA samples.

(21) The GPC instrument can be equipped with a refractive index (RI) detector, a multi-angle laser light scattering (MALLS) detector, a viscometer detector or a combination of the above mentioned detectors.

(22) Alternatively, the molecular weight may be measured by MS methods. A suitable mass spectrometry (MS) method for macromolecules is matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). This technique also provides absolution molecular weight measurement.

(23) Alternatively, the molecular weight may be indirectly expressed as inherent/intrinsic viscosity. Inherent/intrinsic viscosity can be measured with an Ubbelohde viscometer using appropriate solvent.

(24) In a preferred embodiment of the present invention, the Mw of the resulting polymer is at least 5×10.sup.3 Da. More preferably, the molecular weight of the resulting polymer is at least 1.0×10.sup.4 Da. Even more preferably, the molecular weight of the resulting polymer is at least 2.0×10.sup.4 Da. Still more preferably, the molecular weight of the resulting polymer is at least 5.0×10.sup.4 Da, all measured by Gel Permeation Chromatography (GPC).

(25) It is well-known that the ring-opening polymerization of lactide and glycolide is extremely sensitive to the presence of any traces of reactive impurities and, thus, it is difficult to control its polymerization rate and molecular weight progress. Highly pure lactide and glycolide are available in the chemical industry. Alternatively, they may be purified by means of recrystallization, which is a standard purification technique well-known to the skilled person.

(26) The polymerization rate and the molecular weight are also largely affected by the presence of water, because the latter can act both as a co-initiator as well as a chain transfer agent (CTA), lowering the molecular weight of the polymers. Hence the water content of those reaction components should be limited. Many analytical techniques, known to the skilled person, are available to this end. The Karl-Fischer method is suitable for this purpose.

(27) The polymers prepared by the method of the present invention additionally exhibit low polydispersity index.

(28) The method disclosed herein, furthermore, is accompanied by reproducible results. The resulting polymers show repeatable molecular weights and polydispersity index, by applying the same conditions. On the other hand, these properties have been proven to be conveniently controlled by the parameters of the method.

(29) The biodegradable polymers produced according to the method of the present invention may be further employed in a method of production of surgical sutures, implants and drug delivery systems.

(30) The present invention therefore also relates to a method for producing surgical sutures, implants and drug delivery systems, comprising producing a polymer with a method as disclosed herein.

(31) The present invention preferably relates to a method for producing surgical sutures, implants and drug delivery systems, comprising producing a polymer with a method as disclosed herein.

EXAMPLES

(32) All solvents used in the polymerization reaction were dried by means of distillation prior to their use. Monomers were purchased by commercially available sources and no further purification was required. The addition of the initiator and co-initiator solutions was carried out with the aid of flame dried glass syringes, under continuous nitrogen flushing nitrogen conditions, to ensure a strictly anhydrous environment.

(33) Measurement of MW was performed by Gel Permeation Chromatography (GPC) as described below.

(34) Two PLgel columns 5 μm Mixed-D 300×7.5 mm were connected in series (purchased from Agilent). The column temperature applied is 30° C. and the flow rate of the system is 1 mL/min. All samples and standards should be dissolved in Tetrahydrofuran and stirred prior to injection. The suitability of the system is evaluated by five replicate injections of the standard solution of Polystyrene MP 70000. Sample concentration is 4000 μg/mL. The chromatographic procedure includes an injection of blank solution, one injection of each of the polystyrene standards, five injections of system suitability solution, two injections of sample solution and two injections of system suitability solution as QC check (The % RSD of retention time of Polymer peak for five injections of standard solution before sample solution and for two injections of QC check after sample solution should not be more than 1% for retention time. Injection volume of all solutions is 100 μL. MW was calculated using a calibration curve, constructed with polystyrene standards (PolymerLabs) of known molecular weights (purchased from Sigma Aldrich). The calibration curve is a linear first order expression of the elution time to the log (Mw) evaluated by appropriate software.

(35) The inherent/intrinsic viscosity of the produced polymers was measured with an Ubbelohde viscometer (Type 0c). Polymer solutions were prepared in chloroform.

Example 1

(36) In an 9 mL autoclave vial, 0.75 g D,L-lactide (0.0052 mol) and 0.188 g (0.0016 mol) Glycolide were placed under a continuous flow of argon, followed by the addition of 0.000127 g (6.83×10.sup.−7 mol) 1-dodecanol (solution in toluene) and 0.000277 g (6.83×10.sup.−7 mol) Sn(Oct).sub.2 (solution in toluene). 4 mL of toluene was added to the autoclave vial under continuous flow of argon. The autoclave vial was then sealed under argon and immersed into a thermostated oil bath under stiffing at 160° C. After 15 hours, the polymerization reaction was stopped by quenching (i.e., by placing the flask into an ice bath). 10 ml of acetone was added in the autoclave vial to dilute the produced viscous solution under stirring overnight. The diluted solution was transferred in a round bottom flask and evaporated to dryness. The residues were dissolved in 10 ml of acetone under stirring. A sample was withdrawn in order to record a .sup.1H NMR spectrum for the determination of monomers' conversion. The polymer was precipitated by addition of 100 ml of water under stirring in an ice bath. The polymer mass was isolated through vacuum filtration. The precipitated polymer was then dried under vacuum at 60° C. for 24 hours. The total monomer conversion was 97%. The inherent viscosity was 1.36 dL/g measured in chloroform at 25° C. The lactide/glycolide molar ratio determined by .sup.1H NMR was 73:27. The weight averaged molecular weight was 1.60×10.sup.4 Da with a polydispersity index of 1.6 as measured by gel permeation chromatography, using THF as the mobile phase and polystyrene standards.

Example 2

(37) In an 9 mL autoclave vial, 1.5 g D,L-lactide (0.0104 mol) and 0 0.377 g (0.0033 mol) Glycolide were placed under a continuous flow of argon, followed by the addition of 0.000255 g (1.37×10.sup.−6 mol) 1-dodecanol (solution in toluene) and 0.00055 g (1.37×10.sup.−6 mol) Sn(Oct).sub.2 (solution in toluene). 4 mL of toluene was added to the autoclave vial under continuous flow of argon. The autoclave vial was then sealed under argon and immersed into a thermostated oil bath under stirring at 160° C. After 10 hours, the polymerization reaction was stopped by quenching (i.e., by placing the flask into an ice bath). 10 ml of acetone was added in the autoclave vial to dilute the produced viscous solution under stirring overnight. The diluted solution was transferred in a round bottom flask and evaporated to dryness. The residues were redissolved in 10 ml of acetone under stirring. A sample was withdrawn in order to record a .sup.1H NMR spectrum for the determination of monomers' conversion. The polymer was precipitated by addition of 100 ml of water under stiffing in an ice bath. The polymer mass was isolated through vacuum filtration. The precipitated polymer was then dried under vacuum at 60° C. for 24 hours. The total monomer conversion was 98%. The inherent viscosity of this copolymer was 2.26 dL/g measured in chloroform at 25° C. The lactide/glycolide molar ratio determined by .sup.1H NMR was 72:28. The weight averaged molecular weight was 2.70×10.sup.5 Da with a polydispersity index of 1.6 as measured by gel permeation chromatography using THF as the mobile phase and polystyrene standards.

Example 3

(38) In an 9 mL autoclave vial, 0.75 g D,L-lactide (0.0052 mol) and 0.188 g (0.0016 mol) Glycolide were placed under a continuous flow of argon, followed by the addition of 0.00064 g (3.42×10.sup.−6 mol) 1-dodecanol (solution in toluene) and 0.00028 g (6.83×10.sup.−7 mol) Sn(Oct).sub.2 (solution in toluene). 4 mL of toluene was added to the autoclave vial under continuous flow of argon. The autoclave vial was then sealed under argon and immersed into a thermostated oil bath under stirring at 160° C. After 10 hours, the polymerization reaction was stopped by quenching (i.e., by placing the flask into an ice bath). 10 ml of acetone was added in the autoclave vial to dilute the produced viscous solution under stirring overnight. The diluted solution was transferred in a round bottom flask and evaporated to dryness. The residues were dissolved in 10 ml of acetone under stirring. A sample was withdrawn in order to record a .sup.1H NMR spectrum for the determination of monomers' conversion. The polymer was precipitated by addition of 100 ml of water under stiffing in an ice bath. The polymer mass was isolated through vacuum filtration. The precipitated polymer was then dried under vacuum at 60° C. for 24 hours. The total monomer conversion was 97%. The inherent viscosity of this copolymer was 0.79 dL/g measured in chloroform at 25° C. The lactide/glycolide molar ratio determined by .sup.1H NMR was 73:27. The weight averaged molecular weight was 8.92×10.sup.4 Da with a polydispersity index of 1.6 as measured by gel permeation chromatography using THF as the mobile phase and polystyrene standards.

Example 4

(39) In an 9 mL autoclave vial, 0.75 g D,L-lactide (0.0052 mol) and 0.188 g (0.0016 mol) Glycolide were placed under a continuous flow of argon, followed by the addition of 0.00063 g (3.41×10.sup.−6 mol) 1-dodecanol (solution in toluene) and 0.00028 g (6.83×10.sup.−7 mol) Sn(Oct)2 (solution in toluene). 4 mL of toluene was added to the autoclave vial under continuous flow of argon. The autoclave vial was then sealed under argon and immersed into a thermostated oil bath under stirring at 130° C. After 24 hours, the polymerization reaction was stopped by quenching (i.e., by placing the flask into an ice bath). 10 ml of acetone was added in the autoclave vial to dilute the produced viscous solution under stirring overnight. The diluted solution was transferred in a round bottom flask and evaporated to dryness. The residues were redissolved in 10 ml of acetone under stirring. A sample was withdrawn in order to record a .sup.1H NMR spectrum for the determination of monomers' conversion. The polymer was precipitated by addition of 100 ml of water under stiffing in mass was isolated through vacuum filtration. The precipitated polymer was then dried under vacuum at 60° C. for 24 hours. The total monomer conversion was 96%. The inherent viscosity of this copolymer was 0.9 dL/g measured in chloroform at 25° C. The lactide/glycolide molar ratio determined by .sup.1H NMR was 73:27. The produced polymer has a polydispersity index of 1.9 as measured by gel permeation chromatography using THF as the mobile phase and polystyrene standards.

Example 5

(40) In an 9 mL autoclave vial, 0.90 g D,L-lactide (0.0062 mol) and 0.0805 g (0.694 mmol) Glycolide were placed under a continuous flow of argon, followed by the addition of 0.000646 g (3.47×10.sup.−6 mol) 1-dodecanol (solution in toluene) and 0.000281 g (6.94×10.sup.−7 mol) Sn(Oct).sub.2 (solution in toluene). 4 mL of toluene was added to the autoclave vial under continuous flow of argon. The autoclave vial was then sealed under argon and immersed into a thermostated oil bath under stirring at 130° C. After 24 hours, the polymerization reaction was stopped by quenching (i.e., by placing the flask into an ice bath). 10 ml of acetone was added in the autoclave vial to dilute the produced viscous solution under stirring overnight. The diluted solution was transferred in a round bottom flask and evaporated to dryness. The residues were redissolved in 10 ml of acetone under stirring. A sample was withdrawn in order to record a .sup.1H NMR spectrum for the determination of monomers' conversion. The polymer was precipitated mass was isolated through vacuum filtration. The precipitated polymer was then dried under vacuum at 60° C. for 24 hours. The total monomer conversion was 98%. The inherent viscosity of this copolymer was 0.63 dL/g measured in chloroform at 25° C. The lactide/glycolide molar ratio determined by .sup.1H NMR was 87:13. The weight averaged molecular weight was 5.47×10.sup.4 Da with a polydispersity index of 2.5 as measured by gel permeation chromatography using THF as the mobile phase and polystyrene standards.

Example 6

(41) In an 9 mL autoclave vial, 0.75 g D,L-lactide (0.0052 mol) and 0.188 g (0.0016 mol) Glycolide were placed under a continuous flow of argon, followed by the addition of 0.0018 g (9.97×10.sup.−6 mol) glucose (solution in toluene) and 0.00138 g (3.41×10.sup.−6 mol) Sn(Oct).sub.2 (solution in toluene). 4 mL of toluene was added to the autoclave vial under continuous flow of argon. The autoclave vial was then sealed under argon and immersed into a thermostated oil bath under stiffing at 130° C. After 24 hours, the polymerization reaction was stopped by quenching (i.e., by placing the flask into an ice bath). 10 ml of acetone was added in the autoclave vial to dilute the produced viscous solution under stirring overnight. The diluted solution was transferred in a round bottom flask and evaporated to dryness. The residues were redissolved in 10 ml of acetone under stirring. A sample was withdrawn in order to record a .sup.1H NMR spectrum for the determination of monomers' conversion. The polymer was precipitated mass was isolated through vacuum filtration. The precipitated polymer was then dried under vacuum at 60° C. for 24 hours. The total monomer conversion was 98%. The inherent viscosity of this copolymer was 0.33 dL/g measured in chloroform at 25° C. The lactide/glycolide molar ratio determined by .sup.1H NMR was 72:28.